Adiposity and Endometriosis Severity and Typology

Of the 473 women included in the study, 283 had no endometriosis, 112 had stage I, 27 had stage II, 23 had stage III, and 28 had stage IV. While there were no clear associations between a woman’s characteristics and stage of disease, women in our sample with more severe disease were more likely to be older, never been previously pregnant, and from California ( Table 1 ). Among women with endometriosis whose typology was ascertained (n=180), 101 had SE, 34 had DIE, 15 had OE, and 30 had OE + DIE. Women with more severe disease—OE and/or DIE—were more likely to have never been previously pregnant ( Table 2 ). After adjusting for age, race/ethnicity, and pregnancy history, there were no clear differences in adiposity measures in relation to endometriosis stage or typology as evidenced by the overlapping 95% CIs ( Figure 1 and Figure 2 ). However, there were patterns that emerged. Women with endometriosis compared to women without endometriosis overall had the lowest anthropometric/body composition indicator scores ( Figure 1 and 2 ). Among women with endometriosis, women with stages I or IV endometriosis had the lowest anthropometric/body composition indicator scores compared with women diagnosed with stages II or III endometriosis ( Figure 1 ). With regards to typology, a more consistent pattern with severity emerged: women with OE and/or DIE had the lowest anthropometric/body composition indicator scores, while women with SE had the highest scores ( Figure 2 ). Further adjusting for income, marital status, education level, smoking (serum cotinine), alcohol and caffeinated beverage intake, physical activity, and age at menarche did not appreciably alter the estimates.

The primary objectives of the ENDO Study were to 1) estimate the scope and magnitude of endometriosis at both the clinical and population level by diagnostic method and choice of comparison group; and 2) assess the relation of endocrine disrupting chemicals and risk of gynecologic pathology including endometriosis. Women who were enrolled in the operative cohort (n=473) of the ENDO (2007–2009) Study were included in the present analysis [ 1 ]. Women were eligible to participate in the ENDO Study if they were currently menstruating, between the ages of 18 and 44 years, and scheduled to undergo a diagnostic and/or therapeutic gynecologic laparoscopy or laparotomy regardless of clinical indication at one of five participating hospital sites in Salt Lake City, Utah or nine participating clinical centers in San Francisco, California. The primary reasons for surgery among women diagnosed with incident endometriosis were pelvic pain (63%) followed by pelvic mass (14%), menstrual irregularities (11%), suspected fibroids (5%), tubal ligation (4%), and infertility (3%). The primary reasons for surgery among women not diagnosed with incident endometriosis were pelvic pain (31%) followed by pelvic mass (17%), menstrual irregularities, suspected fibroids and tubal ligation (all 14%), and infertility (10%) [ 1 ]. A total of 80 gynecologic surgeons (n=60 in Salt Lake City and n=20 in San Francisco) performed the laparoscopies/laparotomies. Surgeons practiced at a single study site (Salt Lake City or San Francisco) but could practice at multiple clinical centers within a given study site. Women who had a history of a hysterectomy or cancer (except for nonmelanoma skin cancer), had been breastfeeding within the last 6 months, or received injectable hormone treatment within the past 2 years were excluded. Excluded also were women with a history of surgically confirmed endometriosis (prevalent cases) [ 1 ]. This study was approved by the University of Utah and National Institutes of Health Institutional Review Boards for all participating institutions, and all participants gave written informed consent before enrollment and any data collection. Participants completed questionnaires on sociodemographic factors, reproductive history, physical characteristics, medical history, and lifestyle information by computer-assisted, in person interviews approximately two months before surgery. Smoking status was verified by measuring serum cotinine from each participant. Women with serum cotinine ≥ 10 ng/ml were categorized as smokers and those < 10 ng/ml categorized as non-smokers [ 14 ]. Female nurses and research assistants were trained in anthropometric assessment measurements ( Supplemental Figure 1 ) via a standardized protocol. The following measurements were taken during their baseline visit using certified and calibrated equipment [ 13 ]: height (centimeters; cm) with a fixed portable stadiometer (214 Road Rod portable stadiometer [Seca Corporation, Hamburg, Germany; US office, Hanover, MD] or the wooden Shorr Board [Shorr Productions, Olney, MD]); weight (kilograms; kg) with a calibrated electronic balance scale; triceps, subscapular, and suprailiac skinfold thicknesses (millimeters; mm) using a Lange Skinfold Caliper (Beta Technology, Inc., Santa Cruz, CA); and mid-upper arm, waist, and hip body circumferences (cm) using non-stretch tape measures. Chest circumference (cm) was estimated from self-reported bra size using wellestablished algorithms. Bra size was used instead of directly measuring chest size to (a) decrease women’s discomfort that could arise when measuring around the chest and (b) minimize variability in the position of breasts on the chest. Waist circumference measurements were taken by having the participant bend sideways to identify the natural indentation at the waist, identified as the level of the abdomen that is slightly concave (though not in all women). When a participant had no clear natural indentation, the smallest circumference around the waist was taken. To maximize reliability, all measurements were taken twice. If the first two measurements differed by ≥0.5 cm for height, ≥0.1 kg for weight, ≥4 mm for any skinfold thickness, or ≥0.5 cm for body circumferences, then a third measurement was taken and recorded [ 13 ]. Anthropometric measurements were averaged for analysis. Body circumferences were used to derive ratios indicating body fat distribution. Formulas used to derive body composition indicators are as follows: arm fat index = (upper arm fat area/total upper arm area) x 100. BMI was calculated from height and weight measurements (weight (kg) / height (m)2); total upper arm area = mid upper arm circumference (cm)2 /(4 x π); upper arm fat area = total upper arm area - upper arm muscle area; upper arm muscle area = ([mid upper arm circumference(cm)] - [(triceps skinfold thickness[cm]) x π]2 )/(4 x π). BMI categories were defined according to the current recommendations from the Centers for Disease Control and Prevention (CDC, 2017): underweight < 18.5 kg/m2; 18.5 kg/m2 ≤ normal weight < 25.0 kg/m2; 25.0 kg/m2 ≤ overweight < 30.0 kg/m2; and obese ≥ 30 kg/m2. Formulas used to derive body fat distribution ratios were as follows: centripetal fat = subscapular skinfold thickness (mm)/(subscapular skinfold thickness [mm] + triceps skinfold thickness [mm]); chest-to-waist = chest circumference (cm)/waist circumference (cm); chest to-hip = chest circumference (cm)/hip circumference (cm); waist-to-hip = waist circumference (cm)/hip circumference (cm); and waist to-height = waist circumference (cm)/height (cm) [ 13 ]. All participating surgeons of the ENDO study had surgical training in the diagnosis and staging of endometriosis [ 1 , 15 ]. Surgeons completed a standardized operative report immediately after surgery to capture gynecologic and pelvic pathology including extent of endometriosis. Surgeons were first asked to stage endometriosis using a categorical variable ranging from I (minimal) to IV (severe) based on the revised American Society for Reproductive Medicine (rASRM) form. An algorithm automatically calculated the rASRM weighted point score for staging: stage I, minimal (scores 1–5), stage II, mild (scores 6–15), stage III, moderate (scores 16–40), and stage IV, severe (scores >40) [ 16 ]. We used the rASRM weighted point score for staging, with the exception of 5 (3%) of the 190 women who were missing rASRM score and for whom we used surgeon’s initial staging assessment. Our prior research showed substantial agreement between ENDO study gynecologic surgeons on endometriosis diagnosis and staging after viewing digital images and after additionally viewing operative reports [ 15 ]. Participants underwent a single surgery for the ENDO Study. Typology was assessed via the rASRM standardized form, for women whose rASRM form had information on lesion location and size (n=180 [95%] out of the 190 women with an endometriosis diagnosis). Women with only superficial lesions for ovary or peritoneum were considered SE, deep lesions (>5 mm invasion) [ 17 ] noted in the peritoneum or obliteration of posterior cul-de-sac were considered DIE, and deep lesions of any size noted on the ovary were considered OE; women who had deep ovarian and peritoneal lesions were considered OE + DIE. Analyses were largely exploratory and descriptive given that the study was a priori powered for detecting significant differences in serum endocrine disrupting chemicals concentrations by endometriosis status and not for assessing adiposity and endometriosis staging and typology. Adjusted linear mixed models, taking into account within-clinical-center correlation [ 18 ], to generate least square means and 95% confidence intervals (CI) were used to assess differences in endometriosis severity (none, stages I–IV) and typology (none, SE, DIE, OE, OE + DIE) by adiposity measures including height (cm) and weight (kg); skinfold thicknesses (subscapular, suprailiac, and triceps [mm]); circumferences (mid upper arm, chest, waist, and hip [cm]); body composition indicators (arm fat index, BMI, total upper arm area [cm2], upper arm fat area [cm2], and upper arm muscle area [cm2]), and ratios (centripetal fat, chest to waist, chest to hip, waist to hip, and waist to height). The Tukey method was used to test significant mean differences in adiposity measures between each pair of endometriosis staging or typology groups. To supplement P -values, we additionally report 95% CIs keeping in line with latest epidemiologic practice to report interval estimation, which conveys the precision of the estimate with respect to sampling variability [ 19 , 20 ]. Factors known to impact both adiposity and endometriosis risk were considered as potential confounders including age, race/ethnicity, income, marital status, education, smoking (serum cotinine), alcohol and caffeinated beverage intake, physical activity, age at menarche, and pregnancy history. Final multivariable models included adjustments for age (continuous), race/ethnicity (Hispanic, non-Hispanic white, non-Hispanic black, Asian/Pacific Islander/Native American, and other/multiracial), and pregnancy history (no prior pregnancy, prior pregnancy without birth, prior pregnancy with birth). Statistical analyses were performed with SAS software version 9.4 (SAS Institute, Cary, NC), using the PROC MIXED procedure with a random effects statement to take into account variation within-clinical centers across patients.

This is one of the first studies to focus on women’s adiposity and the severity and typology of endometriosis. While the majority of confidence intervals were wide and overlapping, three general impressions emerged: 1) women with versus without incident endometriosis had the lowest anthropometric/body composition indicators; 2) women with stage I or IV had lower anthropometric/body composition indicators compared to women with stage II or III; and 3) women with OE and/or DIE tended to have the lowest anthropometric/body composition indicators, while women with SE had the highest indicators. Prior studies have shown lower BMI and smaller waist-to-hip or waist circumference to be correlated with endometriosis [ 8 , 13 , 21 – 25 ]. Additionally, associations between reduced obesity traits and endometriosis severity have been reported [ 26 ]. We are unique, however, in our assessment of the relationship between validated adiposity measurements (anthropometry, skinfold thickness, limb circumferences, body composition indicators, and body fat distribution ratios) and endometriosis staging and typology. We are aware of only one prior study looking at a single measure of adiposity, BMI, and endometriosis staging [ 11 ]. Among 481 women seen for endometriosis at a university hospital in Korea, women with stages I or II endometriosis had significantly higher BMIs than those with advanced disease stages (III or IV) after adjusting for age, parity, and menstrual history (P<0.001) [ 11 ]. While our results among 190 women with endometriosis revealed that women with stage IV disease had the lowest BMI, we did not find a consistent inverse trend between severity and BMI. Although we adjusted for age, race/ethnicity, parity, and age at menarche, comparison between the Korean and predominately white, non-Hispanic, American populations is difficult. Differences in culture, diet, lifestyle, and (epi)genetic factors that we were not able to control for could impact these associations [ 27 – 30 ]. We are also aware of a single study assessing BMI and endometriosis typology [ 12 ]. Using a case-control study design among women 5 mm under the peritoneal surface), 162 women with pelvic and/or ovarian endometriosis but without deep endometriosis, and 329 control women (women admitted for non-gynecological conditions) and found that women with BMI ≥21 kg/m2 had a lower probability of deep (OR: 0.6 [95% CI: 0.3, 0.8]) or pelvic and/or ovarian endometriosis (OR: 0.6 [95% CI: 0.4, 0.9]) than those with BMI <21 kg/m2 after adjustment for age, marital status, education, smoking, age at menarche, and parity [ 12 ]. Again, comparisons are difficult given the geographic differences and dichotomization of BMI (≥21 versus <21 kg/m 2 ) and typology (deep versus other). Additionally, methodologies for assessing typology differed, given our use of the rASRM form strictly after laparoscopy or laparotomy and their assessment of deep versus not deep endometriosis during laparoscopy or laparotomy or by vaginal or rectal ultrasound examination. However, we similarly categorized women with superficial and deep lesions as deep, and alternative ways of categorizing our sample including removing women with cul de-sac obliteration from deep endometriosis categorization or assuming women with missing typology were of superficial nature did not appreciably alter our findings (data not shown). Future studies with validated methodologies or algorithms for defining typology are needed as endometriosis researchers continue to explore risk factors and symptomology of endometriosis classifications [ 17 ]. While we did find patterns of endometriosis severity (stage IV) and typology (OE and/or DIE) to be associated with the smallest anthropometric and body composition indicators, we were not able to distinguish whether lower adiposity is a cause or consequence of endometriosis. Prior studies have demonstrated that early adult BMI is significantly inversely associated with endometriosis [ 21 ]; however, an animal model suggests that endometriosis might induce weight loss by altered hepatic metabolism [ 32 ]. Future well-designed epidemiologic studies that are adequately powered and capture anthropometric and body composition indicators not only prior to endometriosis diagnosis but prior to disease onset, preferably body habitus from birth through adolescence, are warranted for better understanding true causal relationships between adiposity and endometriosis severity and typology. A number of studies show that BMI may not be the best measure of adiposity [ 33 – 35 ]. A great strength of our study is our use of 19 different adiposity measures: anthropometry, skinfold thickness, circumferences, body composition indicators, and body fat distribution ratios, and expanding our investigation beyond endometriosis diagnosis to endometriosis staging and typology. Nevertheless, our study does have limitations. The study sample included women only from Utah and California, which limits generalizability. Additionally, the predominately overlapping confidence intervals we calculated could be due to an absence of association between adiposity and endometriosis staging or typology or more likely a result of inadequate power to detect such associations, as evidenced by their width. Finally, we may have misclassification bias in endometriosis staging and typology. An ENDO physician reliability study that we previously conducted indicated that expert reviewers, compared to operating surgeons, have a higher probability of diagnosing more mild disease after viewing histology. While we could not confirm whether these patients truly had less severe disease than originally assigned by the operating surgeon or whether the biopsy failed to sample and/or detect disease, we cannot rule out misclassification of disease severity in our study [ 36 ]. However, similar to our findings, prior studies have also found high correlation between visual lesions and pathological confirmation [ 37 , 38 ]. In summary, this is the first study to assess the relationships among a multitude of adiposity measures, severity and typology of endometriosis. While caution is warranted in interpreting our findings due to our limited sample size, an inverse relationship between adiposity, particularly body composition indicators and OE and/or DIE was found among our sample of 473 women participating in the operative cohort of the ENDO study. Our research highlights that the relationship between endometriosis severity and typology with adiposity is more complicated than prior research indicates [ 10 ]. The reason for this potential differential association of endometriosis typology by adiposity measures is not currently known. However, given prior research showing that endometriosis may alter BMI through its effects on adipocytes and fat metabolism, the varying anatomical distribution of adipose tissue may play a role [ 39 ]. Further studies among diverse populations, capturing various adiposity measurements prior to endometriosis diagnosis, and ideally prior to disease development in early adolescence, are needed to better understand the pathogenesis of endometriosis, associations that may indicate systemic involvement and potentially inform preventive strategies.

Endometriosis is an estrogen-dependent gynecologic disease, defined as the presence of endometrial-like tissue outside the uterine cavity, conservatively thought to impact at least 11% of women at the population level [ 1 ]. Endometriosis is recognized as a major cause of infertility and pelvic pain [ 2 , 3 ] and thought to be associated with other disorders characterized by oxidative stress and inflammation, such as ovarian and breast cancers, asthma, autoimmune, cardiovascular, and atopic diseases [ 4 , 5 ]. Despite its relatively high prevalence and impact, endometriosis persists as a clinical enigma due to its controversial etiology, absence of diagnostic biomarkers, and poorly characterized epidemiology. Given that there is currently no cure for endometriosis, identifying pathophysiologic mechanisms and modifiable risk factors remains a key research priority. While some risk factors have been consistently reported—such as early age at menarche and short menstrual cycle length 5 —the impact of various adiposity measures on endometriosis initiation and propagation is not entirely clear. Substantial research demonstrates an inverse relationship between body mass index (BMI) and endometriosis [ 5 – 8 ]. The weight of evidence thus far suggests that endometriosis is associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist [ 9 ]. What is not clear is how a woman’s BMI or adiposity is related to endometriosis severity (e.g., rASRM disease stage) or typology (e.g., superficial endometriosis [SE], deep infiltrating endometriosis [DIE], or ovarian endometrioma [OE]) [ 10 ]. We are aware of only two studies assessing the association between BMI and endometriosis staging or typology [ 11 , 12 ] and none assessing other adiposity measures. In our prior work of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) study, we reported an inverse relationship between adiposity measures (including anthropometry, skinfold thickness, circumferences, body composition indicators, and body fat distribution ratios) and a diagnosis of endometriosis [ 13 ]. Our current study expands on this prior research by assessing the association between BMI, as well as other measures of adiposity, and the severity (minimal, mild, moderate, severe) or typology (SE, DIE, OE) of surgically diagnosed endometriosis.

Supplemental Figure 1: (a) Methodology for performing anthropometric assessments and (b) body composition indicators and body fat distribution ratios calculated using anthropometric measures. Copyright permission is granted by the Journal of Women’s Health, Mary Ann Liebert, Inc., New Rochelle, NY.